PMLBCL : NF-KB Signaling Pathway
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NF-κB Signaling Pathway: NF-κB is a family of dimeric transcription factors involved in inflammatory response, cell proliferation and apoptosis. NF-κB pathway is important in the development, survival, and activation of B-lymphocytes. Aberrant NF-κB activity plays a key role in tumorigenesis and acquired resistance to chemotherapy. NF-κB family includes p65 (RelA) and RelB, c-Rel, p50/p105 (NF-κB1), and p52/p100 (NF-κB2).
Activity of NF-κB proteins is regulated by canonical or alternative pathways. Canonical pathway is activated by multiple stimuli, including tumor necrosis factor (TNF) and interleukin-1 (IL-1) and by bacterial wall lipopolysaccharide (LPS). The alternative or noncanonical pathway is activated by the members of TNF cytokine family (BAFF, CD-40L). Each pathway results in translocation of NF-κB proteins to the nucleus where they activate target gene expression involved in cell survival/apoptosis, cell growth, immune response, and inflammation.
Aberrant NF-κB Activation: Gene expression profiling studies in primary mediastinal large B-cell lymphomas (PMLBCL) have shown overexpression of tumor necrosis factor (TNF) family members that activate NF-κB pathway. Another key protein of NF-κB pathway is REL which is localized to the nucleus. Genomic gains and amplification of chromosome 2p16 (the site of REL protooncogene) are seen in more than 50% of cases of PMLBCL. Constitutive activation of NF-κB pathway in PMLBCL is also mediated via inactivation of negative regulatory feedback mechanisms. TNFAIP3 gene encodes A20 - a negative regulator which inhibits NF-κB signaling downstream of the TNF receptor engagement. This gene is mutated in about 60% of PMLBCL cases leading to constitutive activation of NF-κB pathway.
Figure source: Matthew Martin, Antja-Voy Hartley, Jiamin Jin, Mengyao Sun and Tao Lu (April 24th 2019). Phosphorylation of NF-κB in Cancer, Adenosine Triphosphate in Health and Disease, Gyula Mozsik, IntechOpen, DOI: 10.5772/intechopen.83650. Available from: IntechOpen Books; used under Creative Commons Attribution 3.0 License.
Activity of NF-κB proteins is regulated by canonical or alternative pathways. Canonical pathway is activated by multiple stimuli, including tumor necrosis factor (TNF) and interleukin-1 (IL-1) and by bacterial wall lipopolysaccharide (LPS). The alternative or noncanonical pathway is activated by the members of TNF cytokine family (BAFF, CD-40L). Each pathway results in translocation of NF-κB proteins to the nucleus where they activate target gene expression involved in cell survival/apoptosis, cell growth, immune response, and inflammation.
Aberrant NF-κB Activation: Gene expression profiling studies in primary mediastinal large B-cell lymphomas (PMLBCL) have shown overexpression of tumor necrosis factor (TNF) family members that activate NF-κB pathway. Another key protein of NF-κB pathway is REL which is localized to the nucleus. Genomic gains and amplification of chromosome 2p16 (the site of REL protooncogene) are seen in more than 50% of cases of PMLBCL. Constitutive activation of NF-κB pathway in PMLBCL is also mediated via inactivation of negative regulatory feedback mechanisms. TNFAIP3 gene encodes A20 - a negative regulator which inhibits NF-κB signaling downstream of the TNF receptor engagement. This gene is mutated in about 60% of PMLBCL cases leading to constitutive activation of NF-κB pathway.
Figure source: Matthew Martin, Antja-Voy Hartley, Jiamin Jin, Mengyao Sun and Tao Lu (April 24th 2019). Phosphorylation of NF-κB in Cancer, Adenosine Triphosphate in Health and Disease, Gyula Mozsik, IntechOpen, DOI: 10.5772/intechopen.83650. Available from: IntechOpen Books; used under Creative Commons Attribution 3.0 License.